A versatile drug delivery system targeting senescent cells.

Daniel Muñoz‐Espín,Marta Paez‐Ribes,Stephen G Dann,José Ramón Murguía,Guillermo Garaulet,Alvaro C Ucero,Manuel Serrano,Selim Chaib,Ramón Martínez‐Máñez,Cristina Giménez,Francisca Mulero,Irene Galiana,Andrea Bernardos,David J Shields,Susana Llanos,Beatriz Lozano‐Torres,Miguel Rovira,Maribel Muñoz‐Martín,Todd Vanarsdale

doi:10.15252/emmm.201809355

Abstract

Senescent cells accumulate in multiple aging‐associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β‐galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto‐oligosaccharides. We show that gal‐encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy‐induced senescence, gal‐encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. Moreover, in a model of pulmonary fibrosis in mice, gal‐encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, gal‐encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence‐associated disorders.

Highlights

Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach
Fluorophore-loaded GosNP efficiently release their content within senescent cells, in agreement with the high levels of b-galactosidase activity of these cells (Agostini et al, 2012)
Targeting of senescent cells with GalNP(rho) was validated in three human cancer cell lines treated with palbociclib

Summary

Introduction

Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. We take advantage of the high lysosomal b-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galactooligosaccharides. We show that gal-encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy-induced senescence, gal-encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. In a model of pulmonary fibrosis in mice, gal-encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Gal-encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence-associated disorders

Methods

Results

Conclusion